Human brain function can be probed by measuring the minute currents produced by active neurons using electroencephalography (EEG) and magnetoencephalography (MEG). Neuronal activity also results in localized changes in blood oxygenation and flow, which can be measured using functional magnetic resonance imaging (fMRI). fMRI provides direct localization of brain activation during cognition, but with poor temporal resolution. Conversely, EEG/MEG provides millisecond accuracy, but the location in the brain where they arise is hard to determine. The first aim of this grant is to combine the spatial resolution of fMRI with the temporal resolution of EEG/MEG to produce spatiotemporal maps of brain activation. The accuracy of these maps will be validated using EEG recordings from directly within the brain (conducted in order to localize the seizure focus in patients with pharmaco-resistant epilepsy). These maps will help reveal where and when brain areas are active during thought. The second aim of the grant is to better understand what kind of neuronal activity these maps represent. Linear microelectrode arrays will be used in the same subjects and tasks to estimate population synaptic currents (neuronal inputs) and neuronal firing (outputs) in different cortical layers. The 'activation'found in the whole-brain studies will thus be characterized as excitation vs inhibition, input vs output, and top-down vs bottom-up interactions. The proposed studies should provide insights into how the different brain imaging modalities view functional brain activity, and how they may be integrated in order to trace the passage of activation through the thinking human brain. This technique should also be useful for localizing pathological activity. In addition, the proposed studies may help in the construction of functional neural models for cognition. Such models are necessary to understand how cognition is disrupted in neuropsychiatric disorders. Finally, more complete knowledge regarding the generators of cognitive potentials should greatly increase their value as functional tests for specific brain systems in patients with neurological or psychiatric disease. Specifically, studies on language and memory will provide a scientific basis for the non-invasive mapping of eloquent cortex prior to surgery.